Vertebrate retinas use "fast" (rapidly acting) neurotransmitters to signal moment-to-moment changes in properties of incident light, and "slow" (modulatory) neurotransmitters to regulate signal flow and processing. The long-term goal of this grant is to understand how slow neurotransmitters modulate action potentials that retinas use to encode their input to the brain. This application proposes to examine how the generation of these spikes changes during the course of a normal day by investigating how dopamine regulates voltage-gated ion channels and inhibits spikes in adult rat retinal ganglion cells. Three hypotheses will be tested: (1) dopamine regulates cAMP levels in mammalian retinal ganglion cells; (2) dopamine inhibits mammalian retinal ganglion cells; and (3) dopamine facilitates light-adaptation in mammalian retinal ganglion cells. Hypothesis #1 will be tested by comparing the cAMP-immunoreactivity of ganglion cells in normal and dopamine-depleted retinas, and in dark-adapted retinas after exposure to dopamine receptor agonists. Hypothesis #2 will be tested by comparing the response of alpha and non-alpha types of ganglion cell to dopamine, by examining effects of D1- and D2-type dopamine agonists and related ligands on spikes and ion current in these cells, and by testing whether dopamine receptor activation results in phosphorylation of voltage-gated Na+ channels. Hypothesis #3 will be tested by comparing the responses of ganglion cells in normal and dopamine-depleted retinas to light and to exogenous current injections. These experiments will be performed by electrophysiological, anatomical, and immunohistochemical methods developed specifically to study ion currents and dopamine responses of retinal ganglion cells. The results of these experiments, especially those comparing normal and dopamine-depleted retinas, may help to understand some of the cellular processes that are compromised in retinas during Parkinson's disease, because low retinal dopamine levels have been found in Parkinson's disease, dopamine depletion by neurotoxins has been reported to produce visual deficits like those found in Parkinson's disease, and dopamine produces fundamentally similar responses in retinal ganglion cells of different species.